MALT Lymphoma


Literature Analysis

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  • Immunoglobulin Heavy Chains
  • Molecular Sequence Data
  • Biomarkers, Tumor
  • Chromosome Aberrations
  • Neoplasm Proteins
  • BCL10
  • Helicobacter Infections
  • BIRC3
  • FBXO11
  • Sequence Alignment
  • NF-kappa B
  • Oncogene Fusion Proteins
  • Zinc Fingers
  • Ubiquitin-Protein Ligases
  • Gene Expression Profiling
  • Chromosome 11
  • FOXP1
  • Diffuse Large B-Cell Lymphoma
  • Transcription Factors
  • B-Cell Lymphoma
  • Caspases
  • Transcription Factor RelA
  • Immunohistochemistry
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • BCL2
  • MALT1
  • MYD88
  • FISH
  • fas Receptor
  • Cancer Gene Expression Regulation
  • DNA-Binding Proteins
  • Cancer DNA
  • Nucleic Acid Regulatory Sequences
  • B-Cell CLL-Lymphoma 10 Protein
  • Chromosome 18
  • p53 Protein
  • Stomach Cancer
  • DNA Mutational Analysis
  • Helicobacter pylori and cancer
  • Chromosome 14
  • Eye Cancer
  • Polymerase Chain Reaction
  • Trisomy
  • MALT Lymphoma
  • X-ray Repair Cross Complementing Protein 1
  • Signal Transducing Adaptor Proteins
  • Transcription
  • Sequence Deletion
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (14)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and MALT Lymphoma
BCL2 18q21.33 Bcl-2, PPP1R50 -BCL2 and MALT Lymphoma
FOXP1 3p13 MFH, QRF1, 12CC4, hFKH1B, HSPC215 -FOXP1 and MALT Lymphoma
MYD88 3p22.2 MYD88D -MYD88 and MALT Lymphoma
TNFAIP3 6q23.3 A20, AISBL, OTUD7C, TNFA1P2 -TNFAIP3 and MALT Lymphoma
CD79A 19q13.2 IGA, MB-1 -CD79A and MALT Lymphoma
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and MALT Lymphoma
CARD11 7p22.2 PPBL, BENTA, BIMP3, IMD11, CARMA1 -CARD11 and MALT Lymphoma
BIRC3 11q22.2 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 Translocation
-t(11;18)(q21;q21) MALT1-API2 in MALT lymphomas
-BIRC3 and MALT Lymphoma
IGK 2p12 IGK@ -IGK and MALT Lymphoma
FCRL4 1q23.1 FCRH4, IGFP2, IRTA1, CD307d -FCRL4 and MALT Lymphoma
FBXO11 2p16.3 UBR6, VIT1, FBX11, PRMT9, UG063H01 -FBXO11 and MALT Lymphoma
MALT1 18q21.32 MLT, MLT1, IMD12, PCASP1 Translocation
-t(11;18)(q21;q21) MALT1-API2 in MALT lymphomas
BCL10 1p22.3 CLAP, mE10, CIPER, IMD37, c-E10, CARMEN Translocation
-t(1;14)(p22;q32) in MALT B cell lymphoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Toyoda K, Maeshima AM, Nomoto J, et al.
Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) translocation: long-term follow-up results.
Ann Hematol. 2019; 98(7):1675-1687 [PubMed] Related Publications
Translocation (11;18)(q21;q21) is found in mucosa-associated lymphoid tissue (MALT) lymphoma, resulting in API2/MALT1 gene fusion. It is known that t(11;18)-positive MALT lymphoma shows a tendency to disseminate and be resistant to Helicobacter pylori eradication by antibiotics. However, the prognostic features including recurrence and histological transformation (HT) remain unknown. We conducted a single-institute retrospective analysis of 464 patients with newly diagnosed MALT lymphoma, evaluating the impact of t(11;18) on clinical outcomes. One hundred and six patients were screened for the translocation by fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. Of these patients, 26 patients (25%) were diagnosed as MALT lymphoma with t(11;18). The patients had a significantly shortened progression-free survival (PFS at 10 years; 26% v 57%; P = 0.004) compared to those without t(11;18). However, this did not translate into overall survival or incidence of HT. We confirmed previous reports stating that t(11;18)-positive MALT lymphoma showed disseminated disease and refractoriness to H. pylori eradication therapy. Patients with t(11;18) had more frequent monoclonal gammopathy, especially of IgM subtype (31% v 8%; P = 0.008), some of which developed class switch. These findings characterize the features of t(11;18)-positive MALT lymphoma, suggesting that it comprises a distinct clinical entity of MALT lymphoma.

Caccuri F, Muraro E, Gloghini A, et al.
Lymphomagenic properties of a HIV p17 variant derived from a splenic marginal zone lymphoma occurred in a HIV-infected patient.
Hematol Oncol. 2019; 37(2):176-184 [PubMed] Related Publications
Despite antiretroviral therapy, HIV+ individuals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, which was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117 to 118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicated that HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected individuals where they may act as a local stimulus promoting the development of lymphomas.

Akasaka T, Kishimori C, Maekawa F, et al.
Pulmonary extranodal marginal zone lymphoma that presented with macroglobulinemia and marked plasmacytic cell proliferation carrying the t(14;18)(q32;q21)/MALT1-immunoglobulin heavy-chain fusion gene in pleural fluid.
J Clin Exp Hematop. 2018; 58(3):141-147 [PubMed] Free Access to Full Article Related Publications
An 80-year-old man presented with the accumulation of pleural fluid in the right thoracic cavity. Serum electrophoresis revealed an M-component and immunofixation confirmed IgM/λ. The level of IgM was 1,526 mg/dL. Imaging studies showed an infiltrative condition of the ipsilateral lung parenchyma. The fluid contained abundant neoplastic cells with the morphological and immunophenotypic features of plasma cells, which expressed IgM/λ monoclonal immunoglobulins on the cell surface and in the cytoplasm. The karyotype was 48,XY,+3,add(9)(p13),+12,add(14)(q32),del(16)(q22),-18,+mar, and a series of fluorescence in situ hybridization studies demonstrated that the add(14) chromosome represented der(14)t(14;18)(q32;q21), at which the MALT1-immunoglobulin heavy-chain (IGH) fusion gene was localized. A long-distance polymerase chain reaction amplified the fragment encompassing the two genes, showing that the junction occurred at the J6 segment of IGH and 3.7-kb upstream of the MALT1 breakpoint cluster. We propose that this case represents an extreme form of the plasmacytic differentiation of extranodal marginal zone lymphoma that developed in the lung.

Su Q, Yu GY
[Research progress of salivary glands mucosa-associated lymphoid tissue lymphoma].
Zhonghua Kou Qiang Yi Xue Za Zhi. 2018; 53(1):54-59 [PubMed] Related Publications
Salivary glands mucosa-associated lymphoid tissue lymphoma (SGML) is a distinct subtype of marginal zone B-cell type non-Hodgkin's lymphoma (NHL), which is commonly seen in middle aged females. SGML is usually associated with autoimmune diseases such as Sjögren's syndrome or with chronic infection such as hepatitis C virus (HCV) infection. Chromosomal abnormalities are frequently seen in SGML, which usually activate nuclear factor-κB molecular pathway to modulate cell survival and proliferation, resulting in lymphoma occurrence. SGML tends to arise from parotid gland, presenting frequently as a localized and indolent lesion, a long-term follow-up and biopsy are needed for accurate diagnosis. Surgery, radiotherapy and chemotherapy are usually effective disseminated diseases at multiple sites need combined treatment. SGML has a relatively better prognosis with a higher relapse rate than other types of NHLs, dissemination or higher degree of malignant transformation may occur. Thus, a long-term and close follow-up is essential for patients with SGML.

Zhang Y, Liu A, E M, et al.
Three novel microRNAs based on microRNA signatures for gastric mucosa-associated lymphoid tissue lymphoma.
Neoplasma. 2018; 65(3):339-348 [PubMed] Related Publications
This study aimed to identify novel microRNAs (miRNAs) that play crucial regulatory roles in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma by retrieving and analyzing the miRNA expression profile GSE23877. Differentially expressed miRNAs between gastric MALT lymphoma samples and human tonsil tissue samples as well as their target genes were identified. The transcriptional regulatory relationships between miRNAs and target genes were analyzed, and the regulatory network between them was constructed. Target genes annotated as transcription factors (TFs) were screened, and an miRNA-target gene regulatory network was established. Moreover, the expression levels of miRNAs and target genes as well as the correlation between them were verified. In total, 53 upregulated and 25 downregulated miRNAs were obtained, for which 35 and 25 experimentally validated miRNA-target interactions, respectively, were screened. Some miRNAs were significantly enriched in certain pathways; for example, miR-320a was enriched in systemic lupus erythematosus and ribosome, miR-622 in the p53 signaling pathway and chronic myeloid leukemia, and miR-429 in cancer-related pathways. In addition, upregulated miRNAs, including miR-320a, miR-940, and miR-622, and downregulated miRNAs, including miR-331-3p and miR-429, were hub nodes in the miRNA-target gene regulatory network, and the TF MYC was a co-target of miR-320a, miR-622, and miR-429. The expression trends of miR-320a and miR-429 as well as of some of their target genes were consistent with those in the results of microarray analysis. In conclusion, miR-320a, miR-622, and miR-429 are possibly novel miRNAs participating in the pathomechanism of gastric MALT lymphoma.

Hyeon J, Lee B, Shin SH, et al.
Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement.
Mod Pathol. 2018; 31(9):1418-1428 [PubMed] Related Publications
Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Zhang Y, Yu D, Huang K, et al.
Evaluation of the diagnostic value of immunoglobulin clonal gene rearrangements in patients with parotid gland MALT lymphoma using BIOMED-2 protocol.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 126(2):165-173 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to evaluate the diagnostic value of immunoglobulin (Ig) clonal gene rearrangements for mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland.
STUDY DESIGN: We collected and retrospectively analyzed clinical data of 21 patients referred to our institution between 2009 and 2017. Eight patients had been primarily diagnosed MALT lymphoma of the parotid gland and the remaining patients with lymphoepithelial lesion. Paraffin-embedded tissues were chosen for extracting genomic DNA and multiplex primer polymerase chain reaction amplification by using BIOMED-2 primers. Polymerase chain reaction amplification products were analyzed by heteroduplex analysis.
RESULTS: Generally, 17 patients were identified to have parotid gland MALT lymphoma; 47.06% of them had Sjögren syndrome. The sensitivity of IGH VH-J
CONCLUSIONS: Ig clonal gene rearrangements assays using BIOMED-2 protocol can be a highly reliable diagnostic method for parotid gland MALT lymphoma. For patients with Sjögren syndrome along with histologically benign lymphoepithelial lesion, identification of Ig clonal gene rearrangements is important for routine differential diagnosis.

Pillonel V, Juskevicius D, Ng CKY, et al.
High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations.
Leukemia. 2018; 32(11):2412-2426 [PubMed] Free Access to Full Article Related Publications
Nodal marginal zone lymphoma (NMZL) is a rare small B-cell lymphoma lacking disease-defining phenotype and precise diagnostic markers. To better understand the mutational landscape of NMZL, particularly in comparison to other nodal small B-cell lymphomas, we performed whole-exome sequencing, targeted high-throughput sequencing, and array-comparative genomic hybridization on a retrospective series. Our study identified for the first time recurrent, diagnostically useful, and potentially therapeutically relevant BRAF mutations in NMZL. Sets of somatic mutations that could help to discriminate NMZL from other closely related small B-cell lymphomas were uncovered and tested on unclassifiable small B-cell lymphoma cases, in which clinical, morphological, and phenotypical features were equivocal. Application of targeted gene panel sequencing gave at many occasions valuable clues for more specific classification.

Maurus K, Appenzeller S, Roth S, et al.
Panel Sequencing Shows Recurrent Genetic FAS Alterations in Primary Cutaneous Marginal Zone Lymphoma.
J Invest Dermatol. 2018; 138(7):1573-1581 [PubMed] Related Publications
Primary cutaneous marginal zone lymphoma (PCMZL) represents an indolent subtype of non-Hodgkin lymphoma that is clinically characterized by slowly growing skin tumors with a very low propensity for systemic dissemination. The underlying genetic basis of PCMZL has not been comprehensively elucidated. To gain deeper insight into the molecular pathogenesis of PCMZL, we performed hybridization-based panel sequencing of 38 patients with well-characterized PCMZL. In 32 of the 38 patients, we identified genetic alterations within 39 selected target genes. The most frequently detected alterations (24/38 patients, 63.2%) affected the FAS gene, of which 22 patients harbored alterations, which affect the functionally relevant death domain of the apoptosis-regulating FAS/CD95 protein in a dominant-negative manner. In addition, we identified highly recurrent mutations in three other genes, namely SLAMF1, SPEN, and NCOR2. Our molecular data suggest that apoptosis defects provide the molecular basis of the observed clinical features of PCMZL, which commonly presents with only slowly growing skin tumors, reflecting its invariably indolent behavior. From a diagnostic point of view, highly recurrent FAS mutations in PCMZL presumably separate this indolent lymphoma entity from pseudolymphoma, and this adds adjunctive discriminatory features at a molecular level.

Byford ET, Carr M, Ladikou E, et al.
Circulating Tfh1 (cTfh1) cell numbers and PD1 expression are elevated in low-grade B-cell non-Hodgkin's lymphoma and cTfh gene expression is perturbed in marginal zone lymphoma.
PLoS One. 2018; 13(1):e0190468 [PubMed] Free Access to Full Article Related Publications
CD4+ T-cell subsets are found in the tumour microenvironment (TME) of low-grade B-cell non-Hodgkin's lymphomas such as marginal zone lymphoma (MZL) or follicular lymphoma (FL). Both numbers and architecture of activating follicular helper T-cells (Tfh) and suppressive Treg in the TME of FL are associated with clinical outcomes. There has been almost no previous work on CD4+ T-cells in MZL. It is now recognised that circulating CD4+CXCR5+ T-cells are the memory compartment of Tfh cells. We determined differences in number of circulating Tfh (cTfh) cells and cTfh subsets between normal subjects and patients with FL or MZL. Lymphoma patients showed increased numbers of cTfh1 and reduced cTfh17 cells due to decreased expression of the subset-defining marker CCR6 in patients. PD1, a surface marker associated with Tfh cells, showed increased expression on cTfh subsets in patients. Focusing on MZL we determined expression of 96 T-cell associated genes by microfluidic qRT-PCR. Analysis of differentially expressed genes showed significant differences between normal subjects and patients both for bulk cTfh (CCL4) and the cTfh1 subset (JAK3). While our findings require confirmation in larger studies we suggest that analysis of number and gene expression of circulating T-cells might be a source of clinically useful information as is the case for T-cells within lymphoma lymph nodes.

Thieblemont C
Improved biological insight and influence on management in indolent lymphoma. Talk 3: update on nodal and splenic marginal zone lymphoma.
Hematology Am Soc Hematol Educ Program. 2017; 2017(1):371-378 [PubMed] Free Access to Full Article Related Publications
Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton. Although new therapeutic options based on targeting signaling pathways and overcoming resistance are increasingly available, few specific prospective studies are performed for these rare subtypes, limiting the conclusions that can be drawn. Novel drugs targeting B-cell signaling have shown promise, including ibrutinib and copanlisib. The second-generation oral immunomodalator (IMiD) lenalidomide showed impressive results when combined with rituximab. Other potential solutions include targeting the NF-κB, JAK/STAT, BCL2, NOTCH, and Toll-like receptor signaling pathways; however, studies in these 2 MZL entities are yet to prove a definitive benefit. Molecular profiling is now a cornerstone of diagnostic, prognostic, and therapeutic strategies to offer patient- and disease-specific solutions. The development of a wider range of effective targeted therapies and prognostic biomarkers is keenly awaited and is expected to strongly affect the natural history of SMZL and NMZL.

Agathangelidis A, Xochelli A, Stamatopoulos K
A gene is known by the company it keeps: enrichment of TNFAIP3 gene aberrations in MALT lymphomas expressing IGHV4-34 antigen receptors.
J Pathol. 2017; 243(4):403-406 [PubMed] Related Publications
Associations between immunoglobulin (IG) receptors with distinctive immunogenetic features and particular gene mutations are a recurring theme in mature B-cell lymphomas. Relevant observations have been made in chronic lymphocytic leukemia (CLL), where gene mutations are distributed asymmetrically in cases bearing or not somatic hypermutations within the clonotypic immunoglobulin heavy chain variable region (IGHV) genes (e.g. TP53 mutations predominate in IG-unmutated CLL, whereas the opposite is seen for MYD88 mutations, enriched in IG-mutated CLL) and in subsets of cases with stereotyped IG (enrichment for SF3B1 mutations in CLL subset #2). Moreover, similar findings have been reported in splenic marginal-zone lymphoma, where KLF2 mutations are biased to cases expressing IGHV1-2*04 IG receptors, and in hairy cell leukemia, where IGHV4-34-expressing cases display a low frequency of BRAF mutations but a high frequency of MAP2K1 mutations. The list is now growing with the report of increased frequency of inactivating mutations in the TNFAIP3 gene in MALT lymphomas expressing IG receptors encoded by the IGHV4-34 gene, particularly of the ocular adnexa. Considering that TNFAIP3 encodes a negative regulator of NF-κB, this finding further highlights the importance of NF-κB pathway activation in the natural history of MALT lymphomas. Altogether, these findings allude to selection of genomic aberrations in lymphoma cases with distinctive immune signaling profiles linked to the expression of particular IG receptors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Barth TFE, Kraus JM, Lausser L, et al.
Comparative gene-expression profiling of the large cell variant of gastrointestinal marginal-zone B-cell lymphoma.
Sci Rep. 2017; 7(1):5963 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal (g.i.) large cell lymphoma is currently regarded as diffuse large B-cell lymphoma (DLBCL) despite a more favorable clinical outcome compared to other DLBCL. Cluster analyses on a transcriptome signature of NF-κB target genes of 30 g.i. marginal zone B-cell lymphomas (MZBL; 8 g.i. MZBL, 22 large cell MZBL - among them 9 with coexisting small cell component) and 6 DLBCL (3 activated B-cell like (ABC), 3 germinal center-like (GCB)) reveals a distinct pattern. The distinctiveness of large cell MZBL samples is further confirmed by a cohort of 270 available B-cell lymphoma and B-cell in silico profiles. Of the NF-κB genes analyzed, c-REL was overexpressed in g.i. MZBL. c-REL amplification was limited to 6/22 large cell MZBL including the large cell component of 2/9 composite small cell/large cell lymphomas, and c-Rel protein expression was found in the large cell compartment of composite lymphomas. Classification experiments on DLBCL and large cell MZBL profiles support the concept that the large cell MZBL is a distinct type of B-cell lymphoma.

Moody S, Escudero-Ibarz L, Wang M, et al.
Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4-34 usage in mucosa-associated lymphoid tissue lymphoma.
J Pathol. 2017; 243(1):3-8 [PubMed] Related Publications
Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) usage in 179 MALT lymphomas from various sites. We showed that: (1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 [encoding a global negative regulator of the canonical nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in CD79B, CARD11, MYD88, TNFRSF11A, and TRAF3. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B-cell receptor signalling and driving oncogenesis in lymphoma development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Verdanet E, Dereure O, René C, et al.
Diagnostic value of STMN1, LMO2, HGAL, AID expression and 1p36 chromosomal abnormalities in primary cutaneous B cell lymphomas.
Histopathology. 2017; 71(4):648-660 [PubMed] Related Publications
AIMS: Distinction between primary cutaneous follicular lymphoma (PCFL) and primary cutaneous marginal zone lymphoma (PCMZL) is challenging, as clear-cut immunophenotypical and cytogenetic criteria to segregate both entities are lacking.
METHODS AND RESULTS: To characterize PCFL and PCMZL more clearly and to define criteria helpful for the differential diagnosis, we compared expression of immunohistochemical markers [LIM-only transcription factor 2 (LMO2), human germinal centre-associated lymphoma (HGAL), stathmin 1 (STMN1), activation-induced cytidine deaminase (AID), myeloid cell nuclear differentiation antigen (MNDA)] and the presence of cytogenetic abnormalities described previously in nodal follicular lymphoma [B cell lymphoma 2 (BCL2) and BCL6 breaks, 1p36 chromosomal region deletion (del 1p36)] in a series of 48 cutaneous follicular and marginal zone lymphomas [cutaneous follicular lymphoma (CFL) and cutaneous marginal zone lymphoma (CMZL)]. Immunostaining for STMN1, LMO2, HGAL and AID allowed the distinction between CFL and CMZL, and STMN1 was the most sensitive marker (100% CFL, 0% CMZL). LMO2, HGAL and AID were positive in 93.2%, 82.1% and 86.2% CFL (all CMZL-negative). MNDA was expressed in both entities without significant difference (10.3% CFL, 30.8% CMZL, P = 0.18). BCL2, BCL6 breaks and the del 1p36 were present in 16.7%, 10.7% and 18.5% CFL and no CMZL. Finally, three and 29 CFL were reclassified as secondary cutaneous follicular lymphomas (SCFL) and PCFL without significant differences concerning phenotypical and cytogenetic features. BCL2, BCL6 breaks and the del 1p36 were present in 11.1%, 8% and 16.7% PCFL and did not impact the prognosis.
CONCLUSION: LMO2, HGAL, STMN1 and AID, but not MNDA, are discriminant for the recognition between CFL and CMZL. BCL2, BCL6 rearrangements and the del 1p36 have a role in the pathogenesis of PCFL, the latest being the most common alteration.

Piris MA, Onaindía A, Mollejo M
Splenic marginal zone lymphoma.
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):56-64 [PubMed] Related Publications
Splenic marginal zone lymphoma (SMZL) is an indolent small B-cell lymphoma involving the spleen and bone marrow characterized by a micronodular tumoral infiltration that replaces the preexisting lymphoid follicles and shows marginal zone differentiation as a distinctive finding. SMZL cases are characterized by prominent splenomegaly and bone marrow and peripheral blood infiltration. Cells in peripheral blood show a villous cytology. Bone marrow and peripheral blood characteristic features usually allow a diagnosis of SMZL to be performed. Mutational spectrum of SMZL identifies specific findings, such as 7q loss and NOTCH2 and KLF2 mutations, both genes related with marginal zone differentiation. There is a striking clinical variability in SMZL cases, dependent of the tumoral load and performance status. Specific molecular markers such as 7q loss, p53 loss/mutation, NOTCH2 and KLF2 mutations have been found to be associated with the clinical variability. Distinction from Monoclonal B-cell lymphocytosis with marginal zone phenotype is still an open issue that requires identification of precise and specific thresholds with clinical meaning.

Pileri S, Ponzoni M
Pathology of nodal marginal zone lymphomas.
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):50-55 [PubMed] Related Publications
Nodal marginal zone B cell lymphomas (NMZLs) are a rare group of lymphoid disorders part of the spectrum of marginal zone B-cell lymphomas, which encompass splenic marginal one B-cell lymphoma (SMZL) and extra nodal marginal zone of B-cell lymphoma (EMZL), often of MALT-type. Two clinicopathological forms of NMZL are recognized: adult-type and pediatric-type, respectively. NMZLs show overlapping features with other types of MZ, but distinctive features as well. In this review, we will focus on the salient distinguishing features of NMZL mostly under morphological/immunophenotypical/molecular perspectives in views of the recent acquisitions and forthcoming updated 2016 WHO classification of lymphoid malignancies.

Spina V, Rossi D
Molecular pathogenesis of splenic and nodal marginal zone lymphoma.
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):5-12 [PubMed] Related Publications
Genomic studies have improved our understanding of the biological basis of splenic (SMZL) and nodal (NMZL) marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in these diseases. Consistent with the physiological involvement of NOTCH, NF-κB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL. Beside genetic lesions, also epigenetic and post-transcriptional modifications contribute to the deregulation of marginal zone B-cell differentiation pathways in SMZL and NMZL. This review describes the progress in understanding the molecular mechanism underlying SMZL and NMZL, including molecular and post-transcriptional modifications, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance in SMZL and NMZL.

Arribas AJ, Bertoni F
Methylation patterns in marginal zone lymphoma.
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):24-31 [PubMed] Related Publications
Promoter DNA methylation is a major regulator of gene expression and transcription. The identification of methylation changes is important for understanding disease pathogenesis, for identifying prognostic markers and can drive novel therapeutic approaches. In this review we summarize the current knowledge regarding DNA methylation in MALT lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma. Despite important differences in the study design for different publications and the existence of a sole large and genome-wide methylation study for splenic marginal zone lymphoma, it is clear that DNA methylation plays an important role in marginal zone lymphomas, in which it contributes to the inactivation of tumor suppressors but also to the expression of genes sustaining tumor cell survival and proliferation. Existing preclinical data provide the rationale to target the methylation machinery in these disorders.

Casulo C, Friedberg J
Transformation of marginal zone lymphoma (and association with other lymphomas).
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):131-138 [PubMed] Related Publications
Marginal zone lymphomas (MZL) are a diverse group of indolent lymphoproliferative disorders that comprise three subtypes: nodal, splenic and mucosal associated marginal zone lymphomas (MALT). Histologic transformation (HT) to an aggressive lymphoma is a rare event that can occur in any subtype, and at lower frequency compared to other indolent non Hodgkin lymphomas (NHL) like follicular lymphoma. There are few data directly associated with risk and prognosis of transformation in MZL. However, recent advances in the understanding of molecular and genetic features of MALT have contributed to an evolving appreciation of HT in this disease. Optimal treatment of HT of MZL remains unknown. Much of the approach to managing transformed MZL is extrapolated from other indolent NHLs.

MALT lymphoma: Genetic abnormalities, immunological stimulation and molecular mechanism.
Best Pract Res Clin Haematol. 2017 Mar - Jun; 30(1-2):13-23 [PubMed] Related Publications
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) occurs at diverse anatomic sites and is closely associated with several distinct chronic inflammatory disorders. Both the acquired genetic abnormalities and active chronic immunological responses play a critical role in the development of MALT lymphoma, interestingly by dysregulating similar molecular mechanisms. The three translocations seen in MALT lymphoma, namely t(14;18)(q32;q21)/IGH-MALT1, t(1;14)(p22;q32)/BCL10-IGH, and t(11;18)(q21;q21)/BIRC3 (API2)-MALT1 are capable of activating both canonical and non-canonical NF-κB pathways. TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes its negative regulation to several signalling including BCR and TLR, which activate the canonical NF-κB pathway. Similarly, the immunological responses also activate the canonical NF-κB pathway via surface antigen receptor and TLR, and the non-canonical NF-κB pathway by T-cell help and BAFFR. There is also emerging evidence indicating oncogenic cooperation between the above genetic changes and immunological stimulation in the pathogenesis of MALT lymphoma.

Jung H, Yoo HY, Lee SH, et al.
The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP.
Oncotarget. 2017; 8(10):17038-17049 [PubMed] Free Access to Full Article Related Publications
Ocular marginal zone lymphoma is a common type of low-grade B-cell lymphoma. To investigate the genomic changes that occur in ocular marginal zone lymphoma, we analyzed 10 cases of ocular marginal zone lymphoma using whole-genome and RNA sequencing and an additional 38 cases using targeted sequencing. Major genetic alterations affecting genes involved in nuclear factor (NF)-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B-cell differentiation (23%) were identified. In whole-genome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in 5 samples (50%). In addition, 5 structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region was found in 3 samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), cAMP response element binding proteins (CREBBP) (17%) and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms genes involving in the activation of the NF-kB signaling pathway is the major driver in the oncogenesis of ocular MZL.

Fernández C, Bellosillo B, Ferraro M, et al.
MicroRNAs 142-3p, miR-155 and miR-203 Are Deregulated in Gastric MALT Lymphomas Compared to Chronic Gastritis.
Cancer Genomics Proteomics. 2017; 14(1):75-82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated.
MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real-time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis.
RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis.
CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis.

Kuo SH, Tsai HJ, Lin CW, et al.
The B-cell-activating factor signalling pathway is associated with Helicobacter pylori independence in gastric mucosa-associated lymphoid tissue lymphoma without t(11;18)(q21;q21).
J Pathol. 2017; 241(3):420-433 [PubMed] Related Publications
We previously reported that activation of the B-cell-activating factor (BAFF) pathway upregulates nuclear factor-κB (NF-κB) and induces BCL3 and BCL10 nuclear translocation in Helicobacter pylori (HP)-independent gastric diffuse large B-cell lymphoma (DLBCL) tumours with evidence of mucosa-associated lymphoid tissue (MALT). However, the significance of BAFF expression in HP independence of gastric low-grade MALT lymphomas without t(11;18)(q21;q21) remains unexplored. Sixty-four patients who underwent successful HP eradication for localized HP-positive gastric MALT lymphomas without t(11;18)(q21;q21) were studied. BAFF expression was significantly higher in the HP-independent group than in the HP-dependent group [22/26 (84.6%) versus 8/38 (21.1%); p < 0.001]. Similarly, BAFF receptor (BAFF-R) expression (p = 0.004) and nuclear BCL3 (p = 0.004), BCL10 (p < 0.001), NF-κB (p65) (p = 0.001) and NF-κB (p52) (p = 0.005) expression were closely correlated with the HP independence of these tumours. Moreover, BAFF overexpression was significantly associated with BAFF-R expression and nuclear BCL3, BCL10, NF-κB (p65) and NF-κB (p52) expression. These findings were further validated in an independent cohort, including 40 HP-dependent cases and 18 HP-independent cases of gastric MALT lymphoma without t(11;18)(q21;q21). The biological significance of BAFF signalling in t(11;18)(q21;q21)-negative lymphoma cells was further studied in two types of lymphoma B cell: OCI-Ly3 [non-germinal centre B-cell origin DLBCL without t(11;18)(q21;q21) cell line] and MA-1 [t(14;18)(q32;q21)/IGH-MALT1-positive DLBCL cell line]. In both cell lines, we found that BAFF activated the canonical NF-κB and AKT pathways, and induced the formation of BCL10-BCL3 complexes, which translocated to the nucleus. BCL10 and BCL3 nuclear translocation and NF-κB (p65) transactivation were inhibited by either LY294002 or by silencing BCL3 or BCL10 with small interfering RNA. BAFF also activated non-canonical NF-κB pathways (p52) through tumour necrosis factor receptor-associated factor 3 degradation, NF-κB-inducing kinase accumulation, inhibitor of κB kinase (IKK) α/β phosphorylation and NF-κB p100 processing in both cell lines. Our data indicate that the autocrine BAFF signal transduction pathway contributes to HP independence in gastric MALT lymphomas without the t(11;18)(q21;q21) translocation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Kalpadakis C, Pangalis GA, Vassilakopoulos TP, et al.
Detection of L265P MYD-88 mutation in a series of clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).
Hematol Oncol. 2017; 35(4):542-547 [PubMed] Related Publications
Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL-MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD-88 L265P mutation in a well-characterized series of CBL-MZ to identify cases that may in fact represent WM. Fifty-three CBL-MZ cases were retrospectively evaluated. MYD-88 L265P mutation was determined by allele-specific polymerase chain reaction in blood and/or BM mononuclear cells. Almost half of the CBL-MZ cases (49%) were associated with paraproteinemia mainly of the IgM type (65%). MYD-88 L265P mutation was identified in 10 cases (19%). These cases may truly represent WM, whereas 43 cases (81%) are still classified as CBL-MZ. Mutated cases were all associated with paraproteinemia compared with 37% of the nonmutated ones (P < .0001). In addition, mutated cases displayed more frequently CD38 and CD25 positivity (P = .002 and P = .005, respectively). Moreover, cases without paraproteinemia presented more frequently with lymphocytosis, irrespective of the presence of the MYD-88 mutation (P = .02). The present study demonstrates that MYD-88 L265P mutation may represent the only sensitive marker for the differentiation of CBL-MZ from probable WM. However, further studies are warranted to better define the biological significance of MYD-88 L265P mutation and to clarify whether the presence of the mutation establishes WM diagnosis or that it can also be present in borderline cases associated with paraproteinemia.

Yang WJ, Yu Z, Lyu R, et al.
[IGHV mutational statue in patients with splenic marginal zone lymphoma].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(9):774-778 [PubMed] Related Publications

Johansson P, Klein-Hitpass L, Grabellus F, et al.
Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas.
Oncotarget. 2016; 7(38):62627-62639 [PubMed] Free Access to Full Article Related Publications
The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-κB regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-κB pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-κB signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis. Mutations in NOTCH1 and NOTCH2 were each found in 8% of cases, indicating a pathogenetic function of these factors in OAML. KMT2D was identified as the first epigenetic regulator with mutations in OAML, being mutated in 22% of cases. Mutations in MYD88 were associated with an inferior disease-free survival. Overall, we identified here highly recurrent genetic lesions in components of the NF-κB pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.

MALT lymphoma: A paradigm of NF-κB dysregulation.
Semin Cancer Biol. 2016; 39:49-60 [PubMed] Related Publications
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) invariably arises from a background of chronic microbial infection and/or autoimmune disorder at diverse mucosal sites. The prolonged chronic infection and/or autoimmunity generate active immune and inflammatory responses that provide a setting for evolution and development of autoreactive B-cells, their expansion and eventual malignant transformation following acquisition of genetic changes. The immune responses also play a critical role in sustaining the growth and survival of the transformed cells as shown by complete regression of a high proportion of MALT lymphoma of the stomach, ocular adnexa and skin following anti-microbial treatment. B-cell receptor engagement by auto-antigen as well as T-cell help including both cognate interaction and bystander help via soluble ligands such as CD40L and BAFF are thought to underpin the immunological drive in the lymphoma development through activation of the canonical and non-canonical NF-κB pathway respectively. Similarly, the three MALT lymphoma associated chromosome translocations, namely t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;q21)/IGH-MALT1,and t(11;18)(q21;q21)/BIRC3 (API2)-MALT1, are also capable of activating both canonical and non-canonical NF-κB pathways. Furthermore, TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes the auto-negative feedback to several signalling including BCR and TLR, which connect to the canonical NF-κB activation pathway. Thus, there is a considerable overlap in the molecular pathways dysregulated by immunological drive and somatic genetic changes, strongly arguing for their oncogenic cooperation in the development of MALT lymphoma.

Bahig H, Petrogiannis-Haliotis T, Pehr KL, Roberge D
Primary Cutaneous B-Cell Lymphoma in Young Monozygotic Twins: A Case Report.
J Cutan Med Surg. 2016; 20(6):582-585 [PubMed] Related Publications
Although familial aggregation of lymphoproliferative disorders has been described, heredity has not been implicated in the etiology of primary cutaneous B-cell lymphomas (PCBCL). We report herein the first case of 2 young monozygotic twins with PCBCL. The first twin was an 18-year-old woman when she presented with multiple skin nodules on the thorax and head. Histology showed an atypical small B-cell proliferation, consistent with primary cutaneous marginal zone lymphoma (PCMZL). Molecular genetics studies demonstrated B-cell clonality. Seven years later, the second twin developed her first lesion that was histologically similar to that of her twin. She subsequently developed other clinically similar lesions. Histology was consistent with PCMZL and showed B-cell clonality. Occurrence of PCBCL in these monozygotic twins raises the possibility of a genetic risk factor. Further study of such rare cases may offer valuable insights into the molecular basis of the etiology and pathogenesis of this unusual disorder.

Ozawa MG, Bhaduri A, Chisholm KM, et al.
A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.
Mod Pathol. 2016; 29(10):1212-20 [PubMed] Free Access to Full Article Related Publications
Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
t(1;14)(p22;q32) in MALT B cell lymphomaTranslocationBCL10 (1p22.3)
t(11;18)(q21;q21) MALT1-API2 in MALT lymphomasTranslocationMALT1 (18q21.32)BIRC3 (11q22.2)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. MALT Lymphoma, Cancer Genetics Web: Accessed:

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